Normal aging is typically accompanied by deficits in cognitive domains associated with the function of the hippocampus and temporal lobe. These functional deficits include the loss of spatial and episodic memory, recapitulating the symptoms of damage to the temporal structures. However, not all aged humans develop severe memory loss. The preservation of cognitive function in normal aging can be modeled in rodents using behavioral characterization on tasks that serve as a readout for hippocampal function. This model is useful in identifying mechanisms that are specific to aging, and separating those mechanisms from factors that determine successful or unsuccessful maintenance of cognitive function. A number of developmentally regulated proteins are emerging as mediators of central neuroplasticity in the adult. Among this group, reelin has been identified as a signaling glycoprotein that regulates neuronal positioning during development, and synaptic plasticity in the adult. Reelin localizes to the cytoplasm and extracellular matrix, where it competes with apolipoprotein E (APOE) for activation of the APOE receptor-2 (AP0ER2) and the very low density lipoprotein receptor (VLDLR). Even in the absence of gross developmental abnormalities, interference with reelin signaling through the AP0ER2 impairs hippocampal function at the behavioral and synaptic level. Although several studies now suggest a role for reelin signaling in learning in the adult brain, the contributions of reelin to neuroplasticity in the aging brain are still being elucidated. In our preliminary data, we observed a positive correlation between cognitive function, assessed using the water maze task, and levels of mRNA for the reelin intracellular signaling target, disabled-1 (DAB1) in aged rats. However, the functional significance of changes in reelin signaling with aging has yet to be determined. The studies in this proposal are designed to resolve the contributions of reelin signaling to age-related functional decline. By using both in situ hybridization and immunohistochemistry, we plan to identify the regional contributions to alterations in reelin signaling in the hippocampus and entorhinal cortex. After measuring the regional differences in mRNA and protein for reelin in behaviorally characterized aged rats, we plan to manipulate reelin levels to determine whether entorhinal cortical reelin expression is related to hippocampal learning and memory. The purpose of these studies is to identify novel activity-dependent mechanisms that govern cognitive decline.